scholarly journals Transfection with mRNA for CD19 specific chimeric antigen receptor restores NK cell mediated killing of CLL cells

2009 ◽  
Vol 33 (9) ◽  
pp. 1255-1259 ◽  
Author(s):  
Laurent Boissel ◽  
Monica Betancur ◽  
Winfried S. Wels ◽  
Hande Tuncer ◽  
Hans Klingemann
Keyword(s):  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Antigen Receptor

scholarly journals DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

2015 ◽  
Vol 194 (7) ◽  
pp. 3201-3212 ◽  
Author(s):  
Katrin Töpfer ◽  
Marc Cartellieri ◽  
Susanne Michen ◽  
Ralf Wiedemuth ◽  
Nadja Müller ◽  
...  
Keyword(s):  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Antigen Receptor ◽  
Tumor Immunotherapy ◽  
Cell Tumor

scholarly journals ROR1-Specific Chimeric Antigen Receptor (CAR) NK Cell Immunotherapy for High Risk Neuroblastomas and Sarcomas

2017 ◽  
Vol 23 (3) ◽  
pp. S136-S137 ◽  
Author(s):  
Haein Park ◽  
Aradhana Awasthi ◽  
Janet Ayello ◽  
Yaya Chu ◽  
Stanley Riddell ◽  
...  
Keyword(s):  
High Risk ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Antigen Receptor ◽  
Cell Immunotherapy

scholarly journals Retargeting of natural killer–cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1265-1273 ◽  
Author(s):  
Christoph Uherek ◽  
Torsten Tonn ◽  
Barbara Uherek ◽  
Sven Becker ◽  
Barbara Schnierle ◽  
...  
Keyword(s):  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Killer Cell ◽  
Antigen Receptor ◽  
Antibody Fragment ◽  
Cytolytic Activity ◽  
Antitumoral Activity ◽  
Adoptive Therapy ◽  
Normal Human

The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origins without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92–based therapies, here by transduction with a retroviral vector we have generated genetically modified NK-92 cells expressing a chimeric antigen receptor specific for the tumor-associated ErbB2 (HER2/neu) antigen, which is overexpressed by many tumors of epithelial origin. The chimeric antigen receptor consists of the ErbB2-specific scFv(FRP5) antibody fragment, a flexible hinge region derived from CD8, and transmembrane and intracellular regions of the CD3 ζ chain. Transduced NK-92-scFv(FRP5)-ζ cells express high levels of the fusion protein on the cell surface as determined by fluorescence-activated cell-scanning (FACS) analysis. In europium release assays, no difference in cytotoxic activity of NK-92 and NK-92-scFv(FRP5)-ζ cells toward ErbB2-negative targets was found. However, even at low effector-to-target ratios, NK-92-scFv(FRP5)-ζ cells specifically and efficiently lysed established and primary ErbB2-expressing tumor cells that were completely resistant to cytolytic activity of parental NK-92 cells. These results demonstrate that efficient retargeting of NK-92 cytotoxicity can be achieved and might allow the generation of potent cell-based therapeutics for the treatment of ErbB2-expressing malignancies.

scholarly journals Selective Cytotoxicity of Single and Dual Anti-CD19 and Anti-CD138 Chimeric Antigen Receptor-Natural Killer Cells against Hematologic Malignancies

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Sudjit Luanpitpong ◽  
Jirarat Poohadsuan ◽  
Phatchanat Klaihmon ◽  
Surapol Issaragrisil
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Antigen Receptor ◽  
Antigen Expression ◽  
In Vivo Studies ◽  
Selective Cytotoxicity

Natural killer (NK) cells are part of the first line of defense that rapidly respond to malignant transformed cells. Chimeric antigen receptor- (CAR-) engineered NK cells, although are still at the preliminary stage, have been shown to be alternative to CAR-T cells, mainly due to the absence of graft-versus-host disease and safer clinical profile. Allogeneic human NK cell line NK-92 cells, equipped by CAR, are being developed for clinical applications. Herein, we designed third-generation CARs, optimized the production protocol, and generated CAR-NK-92 cells, targeting CD19 and/or CD138 antigens that employ CD28, 4-1BB, and CD3ζ signaling, with >80% CAR expression, designated as CD19-NK-92, CD138-NK-92, and dual-NK-92 cells. The generated CAR-NK-92 cells displayed high and selective cytotoxicity toward various corresponding leukemia, lymphoma, and multiple myeloma cell lines in vitro. Multitargeting approach using a mixture of CD19-NK-92 and CD138-NK-92 cells was also evaluated at various ratios to test the idea of personalized formulation to match the patients’ antigen expression profile. Our data indicate that increasing the ratio of CD19-NK-92 to CD138-NK-92 could improve NK cytotoxicity in leukemia cells with a relatively higher expression of CD19 over CD138, supporting the personalized proof of concept. This information represents the basis for further in vivo studies and future progress to clinical trials.

Engineering chimeric antigen receptor-natural killer cells for cancer immunotherapy

Immunotherapy ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 653-664 ◽  
Author(s):  
Yu Zhao ◽  
Xiaorong Zhou
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Structural Characteristics ◽  
Antigen Receptor ◽  
Adoptive Cell Transfer ◽  
Antitumor Effects ◽  
Treatment Regimens ◽  
Existing Problems

Adoptive cell transfer has attracted considerable attention as a treatment for cancer. The success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for the treatment of haematologic tumors has demonstrated the potential of CAR. In this review, we describe the current CAR-engineered natural killer (CAR-NK) cell construction strategies, including the design principles and structural characteristics of the extracellular, transmembrane and intracellular regions of the CAR structure. In addition, we review different cellular carriers used to develop CAR-NK cells, highlighting existing problems and challenges. We further discuss possible ways to optimize CAR from the perspective of the tumor microenvironment to harness the strength of CAR-NK cells and provided rationales to combine CAR-NK cells with other treatment regimens to enhance antitumor effects.

scholarly journals CIS checkpoint deletion enhances the fitness of cord blood derived natural killer cells transduced with a chimeric antigen receptor

2020 ◽  
Author(s):  
May Daher ◽  
Rafet Basar ◽  
Elif Gokdemir ◽  
Natalia Baran ◽  
Nadima Uprety ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Aerobic Glycolysis ◽  
Protein A ◽  
Antigen Receptor ◽  
Negative Regulator ◽  
Combined Strategy ◽  
Anti Tumor Activity

AbstractImmune checkpoint therapy has produced remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible SH2-containing (CIS) protein, a key negative regulator of interleukin (IL)-15 signaling, with chimeric antigen receptor (CAR) engineering of natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell anti-tumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that combining CIS checkpoint deletion with CAR engineering promotes the metabolic fitness of NK cells in an otherwise suppressive tumor microenvironment. This approach, together with the prolonged survival afforded by CAR modification, represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.

scholarly journals NK Cell-Mediated Eradication of Ovarian Cancer Cells with a Novel Chimeric Antigen Receptor Directed against CD44

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1339
Author(s):  
Rüdiger Klapdor ◽  
Shuo Wang ◽  
Michael A. Morgan ◽  
Katharina Zimmermann ◽  
Jens Hachenberg ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cytotoxic Activity ◽  
Cancer Cells ◽  
Chimeric Antigen Receptor ◽  
Nk Cell ◽  
Gynecological Cancer ◽  
Antigen Receptor ◽  
Ovarian Cancer Cells ◽  
Ovarian Cancer Stem Cells ◽  
Tumor Spread

Ovarian cancer is the most common cause of gynecological cancer-related death in the developed world. Disease recurrence and chemoresistance are major causes of poor survival rates in ovarian cancer patients. Ovarian cancer stem cells (CSCs) were shown to represent a source of tumor recurrence owing to the high resistance to chemotherapy and enhanced tumorigenicity. Chimeric antigen receptor (CAR)-based adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. In this study, we developed a codon-optimized third-generation CAR to specifically target CD44, a marker widely expressed on ovarian cancer cells and associated with CSC-like properties and intraperitoneal tumor spread. We equipped NK-92 cells with the anti-CD44 CAR (CD44NK) and an anti-CD19 control CAR (CD19NK) using lentiviral SIN vectors. Compared to CD19NK and untransduced NK-92 cells, CD44NK showed potent and specific cytotoxic activity against CD44-positive ovarian cancer cell lines (SKOV3 and OVCAR3) and primary ovarian cancer cells harvested from ascites. In contrast, CD44NK had less cytotoxic activity against CD44-negative A2780 cells. Specific activation of engineered NK cells was also demonstrated by interferon-γ (IFNγ) secretion assays. Furthermore, CD44NK cells still demonstrated cytotoxic activity under cisplatin treatment. Most importantly, the simultaneous treatment with CD44NK and cisplatin showed higher anti-tumor activity than sequential treatment.

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